Selective formylation of alcohols in the presence of phenols with chloral

Primary and secondary alcohols were formylated selectively in the presence of phenols by stirring with chloral in acetone over anhydrous K2CO3 at ambient temperatures in high yields. O-Formylation could be the method of choice for protecting an alcoholic group in a complex synthetic sequence because deformylation can be effected selectively in the presence of acetate or other ester protecting groups. Further, if the alcoholic group is planned to be oxidised later in the synthetic scheme, the formylated alcoholic group need not be deprotected and direct oxidation under Oppenauer conditions can be realised.' In some steroidal transformations, formylation has been found to be superior in detail to acetylation. Formate esters also serve as useful synthetic reagents and intermediates. Despite these uses and considerable potential, the formyl protecting group has been rather overlooked. This is partly due to the fact that efficient formylation procedures under mild conditions are not available. The acid halide or anhydride procedure is unsuitable for formylation because formyl halides and anhydride are unstable. The classical methods of formylation with formic acid with or without an acid catalyst (HCIO4, BF3 ) employ rather drastic conditions. Therefore, several formylation procedures have been reported over the years. These are based on formylation with formic acid in the presence of a dehydrating agent (Ac2O, 7 DCC, l,l'-oxalyldiimidazole), transesterification with methyl/ ethyl formate (catalysed by silica-gel supported metal sulphates, Ce(OTf)4, n Cu(NO3)23H2O, 12 PPh3/CBr4, 13 K5CoW12O40-3H2O ) or with active formates (enol formates, cyanomethyl formate, (3-oxopropyl formate under imidazole or DBN catalysis) and formyl transfer from DMF (in conjunction with benzoyl chloride, SOCl2/LiI, 19 polymer-supported phosphine-halogen complex, secondary bromide/Cs2CO3, ) or from other active A -̂formyl compounds such as A ,̂A^-diformylacetamide, A -̂formyl formamide (generated in situ by ozonolysis of oxazole) as well as A -̂formyl heterocycles (A^-formylbenzotriazole, Af-formylimidazole, A^-formyl-4-pyridone, A^-formyl-2-pyridone, 4-formyl-2-methyl-l,3,4-thiadiazolin-5-thione).Most of these methods, however, use uncommon and in some cases moisture sensitive or thermally unstable reagents which need to be prepared before use, in some cases, by multistep procedures employing expensive catalysts. Many of these methods also suffer from some of the following limitations: elevated temperatures, long reaction times, inert atmosphere, separation of the spent or deformylated reagent, acidic reaction conditions or work up, side reactions, and moderate yields. Chloral reacts with alcohols easily to form stable hemiacetals. It is also known to formylate the primary hydroxy group of methyl mannopyranoside when heated in 1,2-dichloroethane at reflux in the presence of DCC. However, the reaction was not found to be selective and other hydroxy groups reacted differently as shown in Scheme 1.